Contrast agents (or contrast media) are a class of compounds currently employed in various medical imaging techniques to enhance the contrast of structures or fluids within the body.
From a chemical point of view, contrast agents are characterized by structural features, generally dependent on the imaging technique they are intended for. In Magnetic Resonance Imaging (MRI) and in nuclear medicine techniques, both the contrast and the therapeutic agents are usually compounds constituted by a suitable metal ion, chelated by an appropriate chelating agent, so to form a chelated compound (also indicated as paramagnetic complex). To this extent, the common procedures known in the art for the preparation of said complexes foresee the reaction of a chelating agent, usually a polyamino carboxylic acid derivative, with a given metal derivative (e.g. a paramagnetic or a lanthanide metal derivative, or even a radioisotope thereof), in a suitable medium. The chelating agent may be either purchased and used as such, or it may be functionalized or even totally synthesised, for instance, according to procedures known in the art (see among others, WO 00/30688, Bracco).
EP 0230893 discloses the preparation of a series of chelated compounds by reaction of several chelating agents with metal chlorides, in water. In spite of the good yields and reproducibility of the disclosed process the final purification steps are usually carried out in order to remove the residual salts formed during the complexation reaction.
An alternative to this procedure may be represented, for instance, by the reaction of a chelating agent with a metal oxide in lieu of the metal halide, in order to avoid the formation of the afore mentioned salts as side products, (see, for example, EP 0434345, where a paramagnetic complex is prepared by reaction of a tetraazacyclododecane derivative with Gd2O3 in an aqueous solvent system). This methodology however suffers from the problem represented by the low solubility of the starting metal oxide in the reaction medium. Therefore, particular cares have to be devoted to overcome this major issue, such as, e.g., vigorous stirring and high temperatures, with the consequent risk that product degradation or secondary unwanted reactions may occur.
Lever et al. in Nuclear Medicine & Biology, Vol. 23 pp 1013-1017 (1996) describe the labelling of a chelating drug by adsorbing radioactive lead (203Pb) on a Chelex resin, followed by the chelation of the metal by contacting the resin with the chelating drug, i.e., dimercaptosuccinic acid (DMSA) or dibromosuccinic acid (DBSA). However, when the process is carried out using a column method a large excess of chelating agent is necessarily eluted in order to uptake the metal from the resin, with the consequence that a large amount of non-complexed acid is recovered in the final solution along with the radiolabeled complex. On the other hand, in a batch method, the described process occurred with even lower yields.
From all the above it will be apparent that there is still the need of a convenient and generally applicable way, also on industrial scale, for the preparation of chelated compounds in a pure form, in order to avoid the aforementioned drawbacks.
We have now found that when a metal of choice is adsorbed on a solid matrix and an amino carboxylic chelating agent is contacted with said loaded matrix, a corresponding metal chelated compound may be selectively formed, in high yields and in a form substantially free of side products or unreacted material, in a reliable and safe manner.